The present invention relates to methods for producing phenylalanine derivatives having a quinazolinedione skeleton, which are compounds highly useful as drugs having α 4 integrin inhibiting activity, and intermediates thereof.
Recently, research on inflammatory diseases in which α 4 integrin-depending adhesion process participates in the pathology such as rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, tumor metastasis and transplantation rejection has been advanced, and application to treating or preventing agents of the compounds having α 4 integrin inhibiting activity has been expected.
The applicant has already invented new phenylalanine derivatives having α 4 integrin inhibiting activity, which are highly useful as treating or preventing agents for inflammatory diseases in which α 4 integrin-depending adhesion process participates in the pathology and filed a patent application (WO2002-16329).
Conventionally, as the method for producing the phenylalanine derivatives having a quinazolinedione skeleton, it has been reported such as that a quinazolinedione skeleton is constructed via amide intermediates by supporting phenylalanine derivatives on a solid-phase resin (WO2002-16329 and Synlett, 3, 333-336, 2001).
However, though the solid-phase synthesis method has excellent advantages as synthesis of a wide range of derivatives, generally it is not a method suitable for industrialization because the amount of derivatives which can be supported on a solid-phase resin has limitations and, as a result, the amount of the object substance which can be prepared at one time is extremely small. Further, in the solid-phase synthesis, a reaction reagent(s) is generally excessively used, and this is inappropriate from the point of industrialization.
In addition, by substituting the solid-phase synthesis method with a liquid-phase method based on the solid-phase synthesis method, for example, in accordance with well-known examples of reports (S. M. Gadekar, et al., J. Am. Chem. Soc. 4666-4667, 1964, and L. Gouillex, et al., Tetrahedron lett., 37(39), 7031, 1996), a quinazolinedione skeleton can be constructed by a synthesizing method comprising steps of reacting amine with carboxylic acid of anthranilic acid to form an amide, and reacting an amino group of anthranilic acid with ethyl chloroformate, 1,1′-carbonyldiimidazole or the like to make it in carbamate or carbonylimidazolyl form and then forming a quinazolinedione ring with a base(s). However, when the compound is synthesized, it has problems in that the number of reaction processes are large and therefore the yield is low.
On the other hand, as the method via urea intermediates, it has been known such as that amine is reacted with isocyanate to form an urea and a quinazolinedione ring is formed with a base (for example, WO2002-16329 and B. Taub, J. Org. Chem., 26, 5238-5239, 1961).
However, isocyanate is typically a liquid with a pungent odor and highly toxic, and it is known that isocyanate sometimes induces self-polymerization to produce isocyanurate or reacts with water in the air to disintegrate. Thus, isocyanate is typically low in chemical stability and has toxicity.
From these mentioned above, it is needed to find methods for producing phenylalanine derivatives having a quinazolinedione skeleton suitable for industrialization.